Dementing diseases are among the most devastating disorders of aging. Prion diseases are age-dependent, degenerative neurological illnesses and are the focus of this proposal. Much evidence argues that prion diseases are disorders of protein conformation. Computational approaches will be applied to investigate the mechanism of the structural transition during conversion of the cellular prion protein (PrPc) into the scrapie isoform (PrPSc). Our discovery of a PrP deletion mutant consisting of 106 amino acids, denoted PrP106, that supports PrPSc formation and causes prion disease in transgenic (Tg) mice with highly abbreviated incubation times will be exploited for physical studies. PrPSc106 formed in cultured cells i soluble in detergents and as such should be amenable to structural investigations in contrast to full-length PrPSc which is insoluble. Studies to optimize the solubility and purification of PrPSc are proposed. A third approach to determining the tertiary structure of PrPSc utilizes batteries of recombinant antibodies. Recombinant antibodies will also be produced that facilitate the high yield purification of PrPSc106 under non-denaturing conditions. Investigations of a newly recognized form of prion disease in Tg mice and probably humans caused by the accumulation of a transmembrane (TM) form of PrP are planned. We propose to study the pathogenesis of new prion disease caused by the accumulation of Tm PrP and to investigate the pathogenic events in Tg mice expressing PrP106. These investigations will compare mutant PrPs like PrP106 to the wt PrP The diverse skills, talents and backgrounds of the investigators in the proposed program offer an unusual opportunity to define the molecular mechanisms responsible for neurodegeneration and as such provide new approaches to elucidating the etiologies of more prevalent neurodegenerative disorders afflicting older people, including Alzheimer's disease.